The Least Well-Understood Biological Phenomenon
Aging is a complex and little-understood phenomenon. Throughout human history, the etiology of aging has eluded us, but nonetheless captivated our imaginations and piqued our collective curiosities. There exists an enduring sentiment that the aging process is inescapable; like death, growing old is thought to be intrinsic to and inseparable from life. Confounding this, biological age and chronological age do not always correlate. Nature offers a diverse and complex array of aging phenotypes, and there are organisms that seem to exhibit negligible senescence or do not appear to age (de Magalhaes and Costa, 2009). The profound relationship between humans and the aging process is well illustrated by the first recorded work of literature, The Epic of Gilgamesh, whose protagonist embarks on a fruitless quest for immortality. In this vein, the idea of a metaphorical “fountain of youth” has long persisted, but largely been dismissed as a scientific impossibility. In recent centuries, human progress in the realm of hygiene and medicine has led to expectations of a long life, and consequently, expectations of reaching old age, but until very recently, becoming aged was a rarity; for most of our human existence, age itself was not a risk factor for death. This changed with the advent of antibiotics and the ability to combat communicable disease, which led to a greater than 50% increase in human life expectancy since 1900. This rapid increase in human life expectancy over the past 100 years outpaces the increase in life expectancy from the previous 2000; indeed, humans have survived with a life expectancy of 25 years or less for 99.9% of the time we have been a species (Hayflick, 2005). However, living longer and growing older has had unforeseen consequences. Today, age-related pathologies such as cancer, cardiovascular disease, and neurodegeneration are the leading causes of mortality and disability. To combat this, we must achieve a greater understanding of the aging process, which mechanistically underpins all age-related disease. Additionally, a greater understanding of the biology of aging may lead to broader therapeutic strategies to target the aging process itself. To this end, several therapeutic strategies are already being developed, and some have shown exceptional promise by retarding aging in model organisms.
The field of biogerontology is, ironically, quite young. As an emerging discipline, biogerontology lacks a unified agenda concerning the allocation of efforts towards ameliorating aging itself, and similarly, there exists a split among serious biogerontologists concerning the feasibility of doing so. In an effort to focus the debate, some optimistic figures within the field have proposed agendas to this end (see de Grey AD, 2003; de Grey AD 2005). Others believe that “curing” aging is simply too unfocused and unrealistic a task, citing ignorance and overzealous optimism related to unproven interventions (Warner, 2005). Some experts believe that slowing, stopping or reversing aging is akin to violating fundamental laws of physics, and thus will never be accomplished (Hayflick, 2005). Those touting the prospect of anti-aging remedies and therapeutics are routinely characterized as charlatans, and perhaps rightfully so – no panacea for the aging process exists, and no therapeutic intervention has been definitively proven to extend life in humans (Warner, 2005). Recently, this has begun to change. Several therapeutic regimens have shown exceptional promise in retarding aging in model organisms, and for the first time, this knowledge is beginning to be applied successfully to human beings (de Cabo and Madeo, 2014). Whereas aging was once thought of as merely an unprogrammed series of largely random deleterious events, we have now identified genes and pathways that promote longevity; thus, specific cellular pathways likely underpin the aging process (Burgess, 2012). The field of biogerontology is undergoing a renaissance, with an explosion of interest and investment over the past decade. Consequently, we are beginning to develop an understanding of the intricate interplay between the multiple pathways involved in aging. Concurrently, theoretical paradigms for manipulating these pathways are transcending the realm of experimental intractability and becoming increasingly feasible. Key insights include, for example, that the optimization of pathway kinetics towards longevity is not as straightforward as simply driving repair pathways; instead, there is perhaps value in favoring the delicate homeostasis that exists between damage, in a genetic context, and the energy requirement of repair. Emerging too is the vital concept of hormesis, and the further realization that promoting seemingly obvious pathways, for example, telomeric extension, bears its own set of consequences, such as creating an environment conducive to cancer development. While “reversing” aging is still well beyond our reach, the prospects of greatly extending healthspan, life-span and even maximum longevity are becoming increasingly conceivable to some within the field following recent and rapid developments in our understanding of the aging process.
What is aging?
Though seemingly intuitive, aging as a process is difficult to define. In broad terms, human aging has been characterized by a progressive loss of physiological integrity that leads to an impairment of function and an increased risk of death; indeed, aging itself is the most significant risk factor for a plethora of human pathologies including, but not limited to, neurodegeneration, cancer, diabetes and cardiovascular disorders. Following unprecedented advance in the field of aging research over the past decade, Kroemer et al. attempted to unify common denominators of the aging process by enumerating what they termed the “hallmarks of aging”. These nine hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication (Kroemer, 2013). It is well understood that a major challenge for the field is to dissect the interconnectedness between the above hallmarks, with the ultimate goal of identifying pharmacological targets to improve human health during aging. This represents a unique challenge, as aging is one of the most complex and consequently, least well-understood biological processes. As such, the cause of aging is the topic of wide debate. There exist many discreet theories concerning why we age, and consensus on a unified theory of aging has not been reached within the community of biogerontologists. Several attempts have been made to distil the multiplicity of hypotheses on the causes of aging into a cohesive and parsimonious theory, but historically, none have succeeded in garnering unanimous favor in the scientific community (Kirkwood, 2005; Finkel 2005). This is still true today, but we are perhaps closer to a unified understanding of the aging process than ever before. Aging is likely a multifaceted phenomenon for which no single gene or pathway is responsible, but strong evidence exists that suggests that at a basal level, the process is largely driven by destabilizing forces, such as stochastic molecular damage and the intrinsic, adverse side-effects of biochemical pathways. These forces are counteracted by evolved and genetically controlled repair/maintenance processes, and the interplay of these opposing forces may determine lifespan. Thus, aging as a process appears to be the tipping of a delicate homeostasis in favor of damage, as opposed to repair, and there likely exists a balance conducive to longevity.
Central to aging is the concept of genome stability and maintenance, particularly in the form of DNA repair. It is worth noting that of the nine hallmarks proposed by Kroemer et al., genome instability is unique in that it has the propensity to manifest as or exacerbate all other hallmarks. For example, defects in DNA repair, such as those encountered in Cockayne Syndrome (CS; proteins CSB, CSA) result in the activation of PARP1, a signaling protein responsible for recruiting repair factors to single strand breaks (SSBs) in the genome. If these downstream repair factors are incompetent, as is the case in CS, PARP1 binding and consequently, signaling, stay “turned on”. PARP1 signaling requires NAD, a cofactor required for mitochondrial metabolism. Thus, in this case, mitochondrial NAD pools are consumed in defective PARP signaling, allocating resources required for mitochondrial metabolism to faulty DNA damage signaling, thereby causing mitochondrial dysfunction (Bohr, 2014). This resulting mitochondrial dysfunction itself drives the aging phenotype, perpetuating DNA damage by excess reactive oxygen species (ROS) generation, which further damages the genome. This forward-feedback mechanism leads to a vicious, circular cycle capable of further driving the aging phenotype. This is not an isolated incident in the context of segmental Progerias – others, like ataxia telangiectasia (AT) or Bloom Syndrome (BS); both resulting from DNA repair defects – are capable of generating similar phenotypes. Most importantly, it is possible that in the context of “normal” aged individuals, a similar pattern emerges – DNA damage accumulation leads to the driving of mitochondrial dysfunction. In such cases, defects in genome maintenance may causally contribute to aging, as exemplified by accelerated aging disorders, such as segmental progerias and in mice with genetic defects in DNA repair pathways. Furthermore, primary drivers of aging, such as inflammation, have the ability to cause DNA damage, which itself may feedback and cause further secondary aging phenotypes.
In this context, pharmacological and dietary intervention based therapeutic regimens are being developed. These include novel compounds, like nicotinamide riboside (NR) (Fang, 2015) and behavioral interventions such as caloric restriction and a fasting-mimicking diet (FMD) (Longo, 2016). Promise has already been demonstrated with these interventions in mouse models, and on a smaller scale, in human beings, but the next decade will likely lead to definitive answers as to whether or not these interventions has the capacity to be effective in extending health and lifespan.
A Call to Arms
Our need to understand and combat aging is greater now than at any point in history. This represents a universal challenge for mankind, and its importance cannot be understated. The demographics of our global population are changing rapidly and heterogeneously, and the aged are progressively becoming a larger proportion of the population than ever before. Such a shift has serious implications for healthcare, economics, productivity, policy, and society. It was recently estimated that by 2050, 26.9% of the Chinese population, roughly 400 million people, will be over 65 years old. 150 million of these individuals will be 80+ (Fang, 2015). The consequences of such an aged demographic are vast, including a surge in the prevalence and incidence of age-related disease, including cancer, chronic non-communicable diseases (CNCDs) and mental health disorders, among others (Fang, 2015; Wang, 2005; Yang 2008, 2013; Zang and Li, 2011). The economic and social implications of such a shift in age demographics are far-reaching and pose problems of unsustainability. The multifactorial nature of this problem mirrors the multifaceted nature of the aging process, and adequate solutions must tackle the issue both scientifically and socially to succeed. Coping with this change represents perhaps the most pressing challenge for humanity over the next century.
It has been argued that the current focus of medical research on increasing the quantity, rather than the quality of life is damaging our health and harming the economy (Brown, 2014; Mercken 2012). Such a focus exacerbates the problem of an increasingly aged and frail population by increasing lifespan concomitantly with incidence and prevalence of age-related disease. There is a debate within biogerontology concerning the allocation of efforts towards extending healthspan (quality of life over time) versus lifespan (quantity of life over time), but most would tend to agree that healthspan must be extended for lifespan extension to be considered worthwhile. Unfortunately, the current trend of compartmentalizing age-related disease as distinct from the aging process itself has led to a research environment conducive to incremental progress in individual diseases, and thus as a consequence, incremental gains in life expectancy with little improvement in overall healthspan. Some have argued that medical research urgently needs refocusing away from, for example, cancer and cardiovascular research and towards a more streamlined and linear focus on reducing age-related morbidity by targeting aging directly, thereby improving healthspan. Healthspan and lifespan are not mutually exclusive, but an increase in healthspan likely leads to an increase in lifespan, whereas an increase in life expectancy alone increases morbidity due to a consequent rise in age-related disease and dysfunction.
One thing remains clear – the current global rise of age-related disease requires a refocusing on behalf of the scientific and medical community towards a common goal of ameliorating such pathologies in a broad sense. For this to be achieved, we must employ a reductionist approach – a focus on understanding and combating aging, as opposed to treating the symptoms. It has been estimated that if we cured all cancers that affect human beings, the average life expectancy in the US would increase by 4 years, buffered by a massive rise in the incidence of cardiovascular pathology (De Cabo, 2011). This illustrates clearly the importance of a broad and reductionist agenda in biogerontology and the scientific community, in general. We must fight aging; not its manifestations.
Note: This short commentary is adapted from an incomplete review article originally written while the author was a research fellow at The National Institute on Aging in the Laboratory of Molecular Gerontology.
About the Author:
Tyler Golato studied his BSc in biochemistry and molecular biology at Stockton University while spending his summers as a researcher in an experimental therapeutics laboratory at Columbia University under Dr. Robert Fine. After graduation, he embarked on a research fellowship with the National Institute on Aging (NIA/NIH) in the Laboratory of Molecular Gerontology under Drs. David M Wilson III and Vilhelm Bohr. Tyler currently works with the Desmond Tutu HIV Centre at the University of Cape Town, where he coordinates HIV vaccine trials. His goal is to become a physician-scientist.
